Periodontal disease in individuals with diabetes mellitus is more frequent and more severe. Both periodontitis and diabetes patients present with extracellular matrix changes associated with the microvasculature. We propose that changes in the microvasculature are a common, fundamental process in the development of tissue pathology in both Adult Periodontitis and diabetes mellitus, and we offer this as an explanation for the increased incidence and severity of periodontitis in diabetics. Because the plasminogen activators (PA) and their inhibitors, plasminogen activator inhibitors (PAIs) are known to have a critical role in angiogenesis and angiopathies, as well as in extracellular remodeling and fibrinolysis, we propose to demonstrate a significant association of the Pas and PAIs with both periodontitis and diabetes severity, and to show that the exacerbation of periodontitis in diabetics is a function of Pas and PAIs. Diabetes-associated pathology will be measured as the level of diabetic retinopathy, previously demonstrated to correlate with periodontitis severity. Gingival microvasculature changes will be measured by morphometric analysis of histologic sections. We will measure Pas and PAIs in three different ways: genotypes, cellular response levels, and in vivo tissue levels. Our hypothesis states that POA/PAI parameters will be similarly associated with measurements of periodontitis and diabetes pathology but significantly different from levels found in healthy control participants. To address pathophysiology mechanisms which would link changes in PAs and PAIs in three different ways: genotypes, cellular response levels, and in vivo tissue levels. Our hypothesis states that PA/PAI parameters will be similarly associated with control participants. To address pathophysiological mechanisms which would link changes in PAs and PAIs with development of microangiopathy we will use an in vitro endothelial cell microvessel assay system, expression and activation of matrix metalloproteinases, and accumulation of matrix proteins such as type IV collagen and laminin. Anticipated results may focus the targeting of therapeutic intervention for pathology associated with periodontal disease and diabetes mellitus towards the Pas and PAIs and may allow earlier intervention for a patient population determined genotypically to be at risk.